Hypoxia, Lipid Signalling and Tissue Metabolism in Obesity-Related Metabolic Disease

There is a global epidemic of obesity and obesity-related metabolic disorders, such as metabolic syndrome and type-2 diabetes mellitus. While many factors contribute to the aetiology of these conditions, hypoxia is increasingly appreciated to be an important feature of obese tissues, and may be key to the development and progression of metabolic dysregulation. As lipid metabolism is highly dependent on oxygen tension, this work aimed to investigate the links between hypoxia and altered tissue metabolism accompanying the progression of obesity-related metabolic disease, with a particular focus on lipid metabolism. In rat liver, exposure to 2-days environmental hypoxia (10% O₂) resulted in the suppression of sphingomyelin (SM) species. These same SM species were depleted in the liver of obese rats in normoxia, suggesting this is a common signature of the obese and hypoxic liver. The obese liver retained some flexibility to alter metabolism in response to hypoxic exposure, showing a reduction in fatty acid metabolism, however mitochondrial capacity was unaltered in response to hypoxic stress in the obese liver, in contrast to that of lean rats. Cardiac metabolism was more resilient to both hypoxia and obesity, suggesting the liver may be the metabolic “first hit” for these stresses. Mice fed a high-fat high-sugar diet showed a whole-body switch away from glucose towards fatty acid metabolism. The livers of these mice had lower mitochondrial capacities compared with chow-fed mice. As livers became steatotic, there was a decreased capacity to oxidise fatty acids. Supplementing the diets of these mice with inorganic nitrate, a potential therapeutic strategy aiming to improve tissue oxygenation and mitochondrial function via increased nitric oxide bioavailability, resulted in short-term benefits, especially in the heart, where triacylglycerol burden was lowered, but over time resulted in detrimental effects, including increased cardiac fibrosis and greater liver enlargement. In conclusion, there are metabolic signatures common to hypoxia and obesity, specifically in liver, although, some flexibility to respond to hypoxia is retained in obesity. Metabolic derailment in the development of metabolic syndrome and type-2 diabetes is progressive. Short-term inorganic nitrate supplementation may be useful, but over time there are detrimental consequences, which are not countered by the modest metabolic benefits it promotes.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2022

Author dc:creator

• Sowton, Alice

Advisors dc:contributor.advisor

• Murray, Andrew
• Griffin, Julian

• Metabolism
• Obesity
• Type-2 Diabetes
• Non-alcoholic fatty liver disease
• Lipid
• Hypoxia
• Nitrate

Licence

• http://purl.org/NET/rdflicense/allrightsreserved

Language dc:language

eng

Author Identifier

0000-0002-3718-7783

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/342106